NUCLEIC ACIDS SENSOR · Molecular basis of the recognition of foreign nucleic acids in innate immunity

The innate immunity system for vertebrates represents the front-end of their defense against invading viruses and bacteria. Its activation is based on the recognition of pathogen associated molecular patterns (PAMPs) by specialized receptors. Central in the pathogen recognition process is the detection of nucleic acids. However, how exactly foreign nucleic acids are distinguished from host DNA and RNA is poorly understood and of great importance since false recognition leads to severe auto-immune disorders. DAI is a protein which recently was identified as a receptor for dsDNA in the cytoplasm. It belongs to a small family of interferon response related proteins which share DNA/RNA binding domains called Z-domains due to their unusual ability to bind left-handed helices of nucleic acids. Here we propose structural and biochemical work aiming to clarify the molecular basis of the interaction of DAI with nucleic acids as well as to define the role of Z-domains in the context of the interferon inducible RNA editing enzyme ADAR1 and the viral inhibitor of interferon response E3L. This work will build upon extensive crystallographic, NMR and biochemical work on individual isolated Z-domains and aims to clarify how those domains combine and function in the context of the corresponding full length proteins. As part of this work the determination of the structure of DAI in complex with DNA is expected to become a powerful tool for the extensive immunological studies related to the interferon response activation by nucleic acids in the cytoplasm. The work is to be carried out in conjunction at two affiliated institutions: IGC and ITQB both located at Oeiras/Portugal, the first highly respected in immunology and the second in structural biology.